Obesity is an independent risk factor for the development of cardiovascular disease, and the prevalence of obesity is increasing in this country. How obesity causes cardiovascular disease is not understood. Obesity is associated with impaired endothelial function which may play a crucial role in the pathogenesis of cardiovascular disease. The broad, long term objective of this proposal is to investigate the relationship between obesity/insulin resistance and endothelium dependent vasodilation. The specific aims of our proposal are to study changes in endothelial function in response to 1) raising free fatty acid levels, 2) inhibition of sympathetic nervous system activity, and 3) amelioration of insulin resistance. Endothelial function will be determined by assessing the leg blood flow increments in response to intrafemoral artery infusion of the endothelium dependent vasodilator methacholine chloride, the endothelium independent vasodilator sodium nitroprusside, and the inhibitor of endothelium derived nitric oxide NG-monomethyl-L-arginine (L-NMMA). Free fatty acid levels will be raised by systemic infusion of intralipids with heparin. The sympathetic nervous system activity will be inhibited by a femoral artery infusion of phentolamine, an alpha adrenoreceptor blocker. Insulin resistance will be ameliorated by weight loss or by administration of the insulin sensitizer troglitazone. These studies will help to better understand the effect of obesity/insulin resistance on endothelial function and may help to design treatment strategies to decrease the risk for cardiovascular diseases in this population.